Animal models have long predicted that heparin and various heparin derivatives would enhance the efficacy of chemotherapy in the treatment of human cancers. Tani and colleagues, for example, reported that heparin enhances potency of gemcitabine in a pancreatic cancer model (Tani et al., Abstract 4175, Cancer Res. 70(8) (Suppl. 1) (2010)). WO 2012/106379 analogously reports that a substantially non-anticoagulating 2-O, 3-O-desulfated heparin derivative, “ODSH”, improves the efficacy of a chemotherapy regimen that includes gemcitabine in a standard tumor xenograft animal model of human pancreatic cancer.
However, the animal models have proven to be poor at predicting efficacy in human patients, and convincing evidence is sparse that adding heparin or various heparin derivatives enhances efficacy of standard antineoplastic treatment regimens.
For example, despite a wealth of data from both preclinical animal models and early human phase II trials that had suggested that low molecular weight heparin (“LMWH”) significantly prolongs survival in a wide variety of cancers in patients without venous thromboembolism, Maraveyas and colleagues reported in 2012 that adding the LMWH dalteparin to gemcitabine provided no statistically significant improvement in survival in advanced pancreatic cancer in a properly powered trial (Maraveyas et al., Eur. J. Cancer 48:1283-1292 (2012)). In a contemporaneous phase II randomized study, dalteparin could not be shown to improve outcome in ovarian cancer patients being treated with a standard chemotherapy regimen (Elit et al., Thromb Res. 130(6):894-900 (2012)). A few months earlier, van Doormaal et al. had analogously reported that adding the LMWH nadroparin to existing standard of care protocols in patients with advanced prostate, lung, or pancreatic cancer provided no statistically significant survival benefit (van Doormaal et al., J. Clin. Oncol. 29:2071-2076 (2011)).
Similarly, despite the evidence from animal models that ODSH could enhance the efficacy of chemotherapeutic regimens in treatment of pancreatic cancer, no statistically significant benefit in progression-free survival or overall survival was observed in a later human clinical trial testing addition of ODSH to the standard-of-care chemotherapy regimen of gemcitabine plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas (Clinical Trial.gov NCT01461915).
Despite continuing advances in treating cancer, there is still a need in the art for more effective treatments, and for treatments that have fewer side effects.
Myelodysplastic syndromes (“MDS”) represent a spectrum of clonal hematopoietic stem cell disorders characterized by progressive bone marrow failure and increased risk of progression to acute myeloid leukemia (“AML”, also known as “acute myelogenous leukemia”). The International Prognostic Scoring System (“IPSS”) is widely used to identify patients with high risk features based on the severity of their cytopenias, bone marrow myeloblast percentage, and cytogenetic abnormalities. For patients with MDS, allogeneic hematopoietic stem cell transplantation remains the only curative treatment option. However, MDS is a disease of older individuals, with fewer than 5 percent of cases occurring in patients younger than 50 years and the majority being diagnosed at an age over 70 years. Because of age, comorbidities, and other factors, less than 10 percent of all MDS patients are able to proceed to potentially curative allogeneic hematopoietic stem cell transplantation.
Hypomethylating agents are considered standard first line therapy for patients with higher risk disease. Unfortunately, these agents are not curative and only achieve remission in approximately 20-30 percent of patients, with a median duration of response of 8-10 months. Outcomes after hypomethylating agents are poor. There remains an unmet need for better treatment of myelodysplasias.